Abstract
Deregulated pro-survival signalling plays a role in ovarian carcinoma drug resistance. Here, we show that cisplatin or oxaliplatin in combination with the MEK1/2 inhibitor CI-1040 resulted in a synergistic effect associated with enhanced apoptotic response in platinum-sensitive cells. The drug combinations were additive in platinum-resistant cells exhibiting increased phospho-ERK1/2, down-regulation of apoptosis-related factors (BAX, PUMA, FOXO1) and of phosphatases inhibiting ERK1/2 (DUSP5, DUSP6). Consistently, FOXO1 knockdown in sensitive cells reduced the efficacy of the combination treatment. Pharmacological targeting of ERK1/2 pathway increases cell sensitivity to platinum compounds by interfering with multiple events, ultimately favouring apoptosis induction in selected molecular backgrounds.
Original language | English |
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Pages (from-to) | 212-224 |
Number of pages | 13 |
Journal | Cancer Letters |
Volume | 347 |
Issue number | 2 |
DOIs | |
Publication status | Published - Jun 1 2014 |
Keywords
- Drug resistance
- FOXO1
- MEK inhibitors
- Ovarian carcinoma
- Platinum compounds
ASJC Scopus subject areas
- Cancer Research
- Oncology